Many women are infertile, due to surgical removal of their ovaries, premature ovarian failure, exposure to ionizing radiation, toxic chemicals, or drugs, or because of ovaries that have not developed properly, or never developed at all (these women are sometimes hereinafter referred to generally as "functionally agonadal."). Additionally, some women have abnormally low production of hormones, which require exogenous supplemention in order to prevent infertility or early miscarriages.
Various treatments for functionally agonadal women have been developed, including in-vitro fertilization, where the oocyte of a donor is surgically removed from the body, fertizied in a laboratory vessel (in-vitro), and then the fertilized ovum is non-surgically placed into the uterus of the "recipient" woman..sup.1 Additionally, nonsurgical ovum transfer is a recent treatment for these functionally agonadal, infertile, women, involving the nonsurgical recovery of an in vivo fertilized human ovum from a fertile donor, and its nonsurgical transfer to an infertile recipient women..sup.2 Prior to the availability of these donor procedures, there was no possibility of a functionally agonadal woman becoming pregnant.
Previously, an essential step in any of these embryo transfer processes has been the matching of an ovum recipient with a donor who ovulates at about the same time, because the steroid hormone levels in their bloodstreams must be at about the same level for the recipient's body to accept the transfer. Synchronizing ovulation is a complicated procedure, often achieved by having the recipient woman take oral contraceptives and the like. For recipient women whose bodies produce abnormal or insufficient levels of the steroid hormones required for the implantation and proper development of an embryo, some steroid hormone replacement or augmentation is essential if they are to successfully carry the embryo until the pregnancy reaches the luteal-placental shift (i.e. a level of development where the pregnancy itself makes the requisite hormones).
Prior efforts to supply physiologic hormone levels, to women having inadequately low endogenous hormones, or to functionally agonadal women desirous of undergoing an embryo transfer, using various steroid hormone delivery systems, have had significant disadvantages, and may contribute to low efficiency..sup.3 For example, subcutaneous implants for delivery of steroid hormones require surgical insertion and removal, and may provoke deposition of fibrous tissue and alter hormone release rates..sup.4 Crystalline pellets require surgical insertion and are difficult to remove if side effects develop..sup.5 Dermatologic creams,.sup.6 intranasal solutions,.sup.7 oral.sup.8 or sublingual tablets,.sup.9 intramuscular injections and vaginal or rectal suppositories,.sup.10 all result in bolus delivery (i.e. a single massive dose) rather than sustained serum levels, and many of these involve messy, inconvenient, or painful delivery.
The physician3 s therapeutic alternatives for simulation or augmentation of the luteal phase are also limited. Progesterone does not have sufficient activity when given orally, and while still controversial,.sup.11 there appear to be congenital anomalies associated with first trimester administration of synthetic orally active progestins. Thus, the physician's choices appear to be limited to intravaginal and/or intrarectal progesterone suppositories, and intramuscular injections of progesterone in oil.
Silicone rubber (or polysiloxane) has been found to be useful in chronic implants in tissue because it does not cause rejection reactions, even after prolonged periods. It is further known in the art that certain drugs, when incorporated into a device made of polysiloxane, will pass through the polysiloxane carrier and into saline solutions, and when implanted subcutaneously, or placed within a human female's vagina, these drugs will be absorbed into the bloodstream, with a rate of passage dependent on, among other things, the surface area of the material..sup.12 Systemic delivery of contraceptive steroids.sup.13 and replacement of low levels of estradiol in postmenopausal women.sup.14 by polysiloxane vaginal rings has been shown.
There has long been a need for a practical method for establishing physiologic levels of estrogen and progesterone to women with abnormal menstrual cycles, and to functionally agonadal women in order to facilitate donor embryo transfer, which would avoid the vagaries of oral absorption,.sup.15 the effects of oral administration on liver proteins due to initial portal circulation,.sup.16 the use of synthetic hormones which have been associated with birth defects,.sup.17 and the inconvenience of intramuscular injections.